Idiopathic Infantile Hypercalcemia (CYP24A1 Deficiency)
The disease where the body makes too much vitamin D due to a genetic mutation is Idiopathic Infantile Hypercalcemia, caused by biallelic (and sometimes monoallelic) mutations in the CYP24A1 gene, which encodes the enzyme responsible for degrading active vitamin D. 1
Pathophysiology
The condition results from impaired degradation of 1,25-dihydroxyvitamin D [1,25(OH)₂D], the active form of vitamin D, rather than overproduction 1. The mechanism involves:
- Mutations in CYP24A1 gene that encodes 1,25(OH)₂D-24-hydroxylase, the enzyme responsible for breaking down active vitamin D 1
- Accumulation of 1,25(OH)₂D because the body cannot properly degrade it, leading to persistently elevated levels 1
- Both biallelic and monoallelic mutations can cause disease, though biallelic mutations are more commonly symptomatic 1
This differs fundamentally from granulomatous diseases like sarcoidosis, where macrophages produce excessive 1,25(OH)₂D through ectopic 1α-hydroxylase activity 2, 1, 3.
Clinical Manifestations
Patients with CYP24A1 mutations present with 1:
- Elevated serum calcium (hypercalcemia)
- Elevated serum 1,25(OH)₂D levels
- Suppressed PTH concentrations
- Hypercalciuria (excessive calcium in urine)
- Nephrocalcinosis (calcium deposits in kidneys)
- Nephrolithiasis (kidney stones)
- Reduced bone density in some cases
The clinical symptoms of vitamin D toxicity include confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration 4.
Diagnostic Features
The biochemical hallmark distinguishing this from other causes of hypercalcemia 1:
- Elevated 1,25(OH)₂D with suppressed PTH (non-PTH-mediated hypercalcemia)
- Normal or mildly elevated 25(OH)D (unlike vitamin D intoxication where 25(OH)D exceeds 150 ng/ml) 4
- Evidence of impaired 24-hydroxylase activity on metabolic testing
- First-time calcium renal stone formers often show elevated 1,25(OH)₂D with impaired degradation 1
Important Clinical Pitfall
Do not confuse this with vitamin D intoxication from excessive supplementation. In exogenous vitamin D toxicity, 25(OH)D levels exceed 150 ng/ml (375 nmol/L), whereas in CYP24A1 deficiency, the primary elevation is in 1,25(OH)₂D with relatively normal 25(OH)D 1, 4. The mechanism is fundamentally different: impaired degradation versus excessive intake.
Related Conditions with Excessive Vitamin D Production
Other conditions with dysregulated vitamin D metabolism include 1, 3, 5:
- Granulomatous diseases (sarcoidosis, tuberculosis): Macrophages produce excessive 1,25(OH)₂D through unregulated 1α-hydroxylase activity
- Lymphomas: Tumor cells may produce ectopic 1,25(OH)₂D
- Williams-Beuren syndrome: Congenital disorder with excessive production of both 25(OH)D and 1,25(OH)₂D